Neutralisation of Peritoneal IL-17A Markedly Improves the Prognosis of Severe Septic Mice by Decreasing Neutrophil Infiltration and Proinflammatory Cytokines
Purpose The current study aimed to elucidate the role of peritoneal fluid IL-17A in septic mice, and the effects of intraperitoneal or intravenous blockade of the IL-17A pathway by anti-IL17A antibody on survival, plasma, and peritoneal cavity cytokine profile in a murine caecal ligation and puncture (CLP) sepsis model. The main source of peritoneal fluid IL-17A in septic mice was identified. Methods Male C57BL/6 mice that underwent severe CLP or sham surgery were intraperitoneally or intravenously administered anti-IL17A antibodies or isotype antibodies. The survival rates were observed. IL-17A, TNF-α, and IL-6 cytokine levels were measured by ELISA. Surface and intracellular IL-17A immunofluorescence stains were detected by flow cytometry to identify the IL-17A–producing cells. Results The IL-17A level was elevated much higher and earlier in peritoneal fluid than in the blood of the CLP mice. The intraperitoneal IL-17A blockade more significantly protects against CLP-induced mortality than intravenous blockade because of decreased TNF-α and IL-6 levels both in peritoneal fluid and blood, neutrophil infiltration in the peritoneal cavity, and lung injury. γδ T lymphocytes were identified to be the main source of IL-17A in the peritoneal fluid of septic mice. Conclusions The earlier and higher elevated IL-17A derived from γδ T cells in peritoneal fluid plays a critical role during polymicrobial severe sepsis and effect of intraperitoneal IL-17A antibody administration superior to intravenous administration on survival of severe CLP-induced septic mice. The intraperitoneal blockade of IL-17A decreases proinflammatory cytokine production, neutrophil infiltration, and lung injury, thereby improving septic mice survival, which provides a new potential therapy target for sepsis.
References
[1]
Deans KJ, Haley M, Natanson C, Eichacker PQ, Minneci PC (2005) Novel therapies for sepsis: a review. J Trauma 58(4): 867–874.
[2]
Riedemann NC, Guo RF, Ward PA (2003) The enigma of sepsis. J Clin Invest 112(4): 460–467.
[3]
Baue AE, Durham R, Faist E (1998) Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle? Shock 10(2): 79–89.
[4]
Faist E, Kim C (1998) Therapeutic immunomodulatory approaches for the control of systemic inflammatory response syndrome and the prevention of sepsis. New Horiz 6(2 Suppl): S97–102.
[5]
Kasten KR, Tschop J, Adediran SG, Hildeman DA, Caldwell CC (2010) T cells are potent early mediators of the host response to sepsis. Shock 34(4): 327–336.
[6]
Bosmann M, Ward PA (2012) Role of C3, C5 and anaphylatoxin receptors in acute lung injury and in sepsis. Adv Exp Med Biol 946: 147–159.
[7]
Bone RC (1996) Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med 125(8): 680–687.
[8]
Shubin NJ, Monaghan SF, Ayala A (2011) Anti-inflammatory mechanisms of sepsis. Contrib Microbiol 17: 108–124.
[9]
Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27: 485–517.
[10]
Miossec P, Korn T, Kuchroo VK (2009) Interleukin-17 and type 17 helper T cells. N Engl J Med 361(9): 888–898.
[11]
Kolls JK, Linden A (2004) Interleukin-17 family members and inflammation. Immunity 21(4): 467–476.
[12]
Dejager L, Pinheiro I, Dejonckheere E, Libert C (2011) Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol 19(4): 198–208.
[13]
Vianna RC, Gomes RN, Bozza FA, Amancio RT, Bozza PT, et al. (2004) Antibiotic treatment in a murine model of sepsis: impact on cytokines and endotoxin release. Shock 21(2): 115–120.
[14]
Zhang Y, Zhou Y, Lou J, Li J, Bo L, et al. (2010) PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Crit Care 14(6): R220.
[15]
Tanino Y, Makita H, Miyamoto K, Betsuyaku T, Ohtsuka Y, et al. (2002) Role of macrophage migration inhibitory factor in bleomycin-induced lung injury and fibrosis in mice. Am J Physiol Lung Cell Mol Physiol. 283(1), L156–L162.
[16]
Xu KF, Shen X, Li H, Pacheco-Rodriguez G, Moss J, et al. (2005) Interaction of BIG2, a brefeldin A-inhibited guanine nucleotide-exchange protein, with exocyst protein Exo70. Proc Natl Acad Sci U S A 102(8): 2784–2789.
[17]
Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25: 821–852.
[18]
Hayday A, Tigelaar R (2003) Immunoregulation in the tissues by gammadelta T cells. Nat Rev Immunol 3(3): 233–242.
[19]
Roark CL, Simonian PL, Fontenot AP, Born WK, O'Brien RL (2008) gammadelta T cells : an important source of IL-17. Curr Opin Immunol20(3): 353–357.
[20]
Hayday AC (2000) [gamma][delta] cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol 18: 975–1026.
[21]
Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, et al. (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126(6): 1121–1133.
[22]
Lochner M, Peduto L, Cherrier M, Sawa S, Langa F, et al. (2008) In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells. J Exp Med 205(6): 1381–1393.
[23]
Freitas A, Alves-Filho JC, Victoni T, Secher T, Lemos HP, et al. (2009) IL-17 receptor signaling is required to control polymicrobial sepsis. J Immunol 182(12): 7846–7854.
[24]
Flierl MA, Rittirsch D, Gao H, Hoesel LM, Nadeau BA, et al. (2008) Adverse functions of IL-17A in experimental sepsis. FASEB J 22(7): 2198–2205.
[25]
Chung CS, Watkins L, Funches A, Lomas-Neira J, Cioffi WG, et al. (2006) Deficiency of gammadelta T lymphocytes contributes to mortality and immunosuppression in sepsis. Am J Physiol Regul Integr Comp Physiol 291(5): R1338–1343.
[26]
Tschop J, Martignoni A, Goetzman HS, Choi LG, Wang Q, et al. (2008) Gammadelta T cells mitigate the organ injury and mortality of sepsis. J Leukoc Biol 83(3): 581–588.
